Focus on 2010 ESC Congress: new ESC guidelines and data on dabigatran.

In a major symposium on atrial fibrillation (AF), Prof John Camm, head of the Department of Cardiac and Vascular Sciences at St Georges, University of London, pointed out that atrial fibrillation cases are set to double as populations age. ‘One in four adults 40 years of age will develop atrial fibrillation in their lifetime. The consequences are tragic and devastating, with a five-fold increase in the risk of having a stroke’, he said. Stroke is also more likely to be severe and fatal in these patients; those who survive face persistent neurological deficits, persistent disability and poorer functional performance. The European Society of Cardiology (ESC) has now issued revised practice guidelines for the management of atrial fibrillation, including guidance on the role of a novel oral treatment, dabigatran etexilate, for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Dr Jeffrey Friedman, therapeutic head of cardiovascular products at Boehringer Ingelheim in the USA confirmed that the US Food and Drug Administration (FDA) has granted a priority review designation for dabigatran etexilate for the prevention of stroke in AF. A priority review designation is given to new drugs that are expected to offer major advances in treatment, or provide a treatment where no adequate therapy exists. (An FDA advisory committee met on September 20 to review and discuss dabigatran etexilate data.)* In addition to the USA, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive marketing authorisation for dabigatran etexilate in these countries by the end of 2010 or the beginning of 2011. Dr Friedman pointed out that Boehringer Ingelheim has a long-term commitment to stroke prevention, with the development of Actilyse in 1982, Asasantin retard in the 1990s, and more recently, Micardis for the prevention of stroke and myocardial infarctions in the early 2000s. ‘Telmisartin is still the only ARB with a broad claim for cardiovascular protection, based on the ONTARGET studies’, Dr Friedman noted. Discussing the latest RELY results, Dr Jonas Oldgren from the Uppsala Clinical Research Centre, pointed out that all centres, even those with poorer INR control determined from their patients’ time-in-treatment data, achieved better results using dabigatran than warfarin in the reduction of stroke and systemic embolism. As might be expected in the poorer warfarin-control setting, both dosages of dabigatran demonstrated superior advantages over warfarin in the reduction of secondary outcomes, such as the composite of all cardiovascular events, total mortality and major bleeding. The secondary outcome results in centres with better INR control were comparable between dabigatran and warfarin. ‘Local standards of care do therefore affect the benefits of switching to new treatment strategies’, Prof Oldgren said. For each patient involved in the warfa-


AFRICA focus on 2010 EsC Congress new EsC guidelines and data on dabigatran
In a major symposium on atrial fibrillation (AF), Prof John Camm, head of the Department of Cardiac and Vascular Sciences at St Georges, University of London, pointed out that atrial fibrillation cases are set to double as populations age. 'One in four adults 40 years of age will develop atrial fibrillation in their lifetime. The consequences are tragic and devastating, with a five-fold increase in the risk of having a stroke', he said. Stroke is also more likely to be severe and fatal in these patients; those who survive face persistent neurological deficits, persistent disability and poorer functional performance. 1,2 The European Society of Cardiology (ESC) has now issued revised practice guidelines for the management of atrial fibrillation, including guidance on the role of a novel oral treatment, dabigatran etexilate, for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Dr Jeffrey Friedman, therapeutic head of cardiovascular products at Boehringer Ingelheim in the USA confirmed that the US Food and Drug Administration (FDA) has granted a priority review designation for dabigatran etexilate for the prevention of stroke in AF. A priority review designation is given to new drugs that are expected to offer major advances in treatment, or provide a treatment where no adequate therapy exists. (An FDA advisory committee met on September 20 to review and discuss dabigatran etexilate data.)* In addition to the USA, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive marketing authorisation for dabigatran etexilate in these countries by the end of 2010 or the beginning of 2011.
Dr Friedman pointed out that Boehringer Ingelheim has a long-term commitment to stroke prevention, with the development of Actilyse in 1982, Asasantin retard in the 1990s, and more recently, Micardis for the prevention of stroke and myocardial infarctions in the early 2000s. 'Telmisartin is still the only ARB with a broad claim for cardiovascular protection, based on the ONTARGET studies', Dr Friedman noted.
Discussing the latest RELY results, 3 Dr Jonas Oldgren from the Uppsala Clinical Research Centre, pointed out that all centres, even those with poorer INR control determined from their patients' time-in-treatment data, achieved better results using dabigatran than warfarin in the reduction of stroke and systemic embolism.
As might be expected in the poorer warfarin-control setting, both dosages of dabigatran demonstrated superior advantages over warfarin in the reduction of secondary outcomes, such as the composite of all cardiovascular events, total mortality and major bleeding. The secondary outcome results in centres with better INR control were comparable between dabigatran and warfarin. 'Local standards of care do therefore affect the benefits of switching to new treatment strategies', Prof Oldgren said.
For each patient involved in the warfa-

*stop press fda meeting on dabigatran
One of cardiology's fondest wishes moved closer to fulfillment as an FDA advisory panel unanimously recommended approval of a potential replacement for warfarin in one of the most common heart disorders. Barring any unforeseen damning revelations about the drug, the FDA's approval of the oral thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation is all but certain. The panel, with its nine voting members, made the decision based on what's generally seen as the well-designed, solidly executed, 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, which showed dabigatran was non-inferior to warfarin at a lower dosage and superior at a higher one for preventing thromboembolic stroke in paroxysmal or permanent AF.
Debate among the advisory panel throughout the day was tame; there were few criticisms of the RELY trial's design, little disappointment in the results, and clear enthusiasm for replacing warfarin in such a widespread indication.
The panel wasn't charged with voting on a question that provided some of the only suspense throughout the day; whether the approval should include only the higher dose, which demonstrated superiority in RELY, or perhaps both dosage levels. They voted informally nonetheless, with those expressing a preference for both dosages (generally wanting to give clinicians more flexibility) edging out those favouring only the higher dose. Some of the latter panelists felt the lower dose would become the default for clinicians concerned about safety but at the expense of efficacy.
Warfarin is distinguished as being one of the oldest, most widely used, most effective, and most disliked drugs in cardiology: it dramatically cuts ischaemic stroke risk in AF but generally requires tight anticoagulation monitoring to get the dosage right, which can be arduous for patients and the healthcare system. Patients must also banish a lot of healthy, vitamin K-containing foods from their diet.
The kicker with dabigatran, even when 'non-inferior' to warfarin, is that it doesn't require anticoagulation monitoring, or major diet changes, for that matter. And, as the trial suggested and some panelists agreed, at the higher dose it seems more stroke-preventive than warfarin.
As previously reported by heartwire, RELY compared the two dabigatran dosage levels against a conventional warfarin regimen for the strokeprevention indication. Dabigatran was non-inferior to warfarin at the lower dosage and superior at the higher one, the latter achieving a 34% decline in risk (p < 0.001) over a median of two years.

Rivaroxaban protection is non-inferior and safe when compared to low-molecular weight heparin and warfarin
Results from the EINSTIEN-DVT trial were announced at the recent ESC 2010 congress, showing the therapeutic equivalence of rivaroxaban (15 mg twice daily for three weeks, followed by 20 mg once daily) to current standard therapy in treating and preventing further venous thrombotic events (VTE).
Prof Harry Buller, Academic Medical Centre, Amsterdam presented the results in the hot-line session and pointed out that this trial is the largest ever undertaken in deep-vein thrombosis (DVT), with 3 449 patients entered into the study from 32 countries.
'EINSTEIN-DVT was designed as a non-inferiority trial and although open label, all events were adjudicated blindly. The primary-efficacy outcome was defined as symptomatic recurrent VTE: composite of recurrent DVT, non-fatal or fatal pulmonary embolism (PE)', he said.
This trial has now shown that rivaroxaban taken orally is as effective in preventing recurrence of symptomatic VTE as well-managed patients receiving the current standard therapy of injectable low-molecular weight heparin (LMWH), enoxaprin or fondaparinux, and an oral vitamin K antagonist, chiefly warfarin.
While scientific publication of the full results will still follow, Prof Buller presented substantiating data for the conclusions. 'The first symptomatic recurrent VTE occurred in 3% of patients receiving standard therapy, compared to 2.1% on rivaroxaban (hazard ratio of 0.68). This difference was significant and reached our preset standard for non-inferiority', he said.
'Importantly, there was no difference in the principal safety outcome, measuring a composite of major and non-major clinically relevant bleeding events (8.1% in both treatment arms). Rivaroxaban did however show a tendency to cause fewer major bleeds (14 in the rivaroxaban arm and 20 in the enoxaparin/warfarin arm)', Prof Büller said. Net clinical benefit, a parameter of primary efficacy plus no major bleeding, favours rivaroxaban therapy.
Overall control of patients receiving enoxaprin and vitamin K antagonists was good, with 57% within the targeted INR range of 2 to 3, and this increased to 60% at three months after the trial. The trial was conducted over a 12-month period.
Discussing the results, Eve Knight of Anti-Coagulant Europe, the non-profit organisation that represents the interests of patients who have to take anti-coagulant therapy following a VTE, pointed out that patients have great difficulty with the cumbersome warfarin therapy.
'You are continually having to visit the clinic and have blood drawn for INR monitoring. You have to watch your food and drink intake, which greatly impacts on quality of life. VTEs affect young people who are still very active, the patients in the EINSTEIN trial were about 56 years of age, causing ongoing disruption to one's working life and can affect career progress very badly', she stressed.
Rivaroxaban is available in South Africa for the prevention of DVT following orthopaedic surgery and Bayer will be making representation to regulatory authorities across the world for the use of this drug in treating both primary and secondary DVT. 'As this drug has the potential to change clinical practice, it may well receive priority attention', Dr Berkowitz, Bayer Schering Pharma medical director noted. rin arm of the RELY trial, the quality of warfarin treatment was calculated by establishing the time in therapeutic range (TTR). The average individual time in therapeutic range (iTTR; with a target INR of 2.0-3.0) for patients randomised to warfarin was 64%, which is a similar level of control to that seen in recently published prospective, randomised trials.
There were considerable variations in TTR among the trial centres across the 44 participating countries. In the present sub-group analysis, each centre's average TTR (cTTR) was calculated as the average of all individual patients' TTRs in the warfarin group.
The distribution of cTTRs across study centres was investigated and interquartile limits were identified. The quartiles of cTTR for the warfarin patients were